Jingnian Ni

Screening mild cognitive impairment by delayed story recall and instrumental activities of daily living.

Dementia has been a major public health problem, and mild cognitive impairment (MCI) has been recognized as an object of secondary prevention especially for Alzheimer’s disease. The pooled prevalence of MCI for the elderly population was 12.7% in China (Nie et al., 2011). Amnestic MCI is the main type, approximately 80% of which converted to dementia in a 6-year follow-up (Petersen, 2004). The previous study found delayed story recall (DSR) was a useful tool for differentiating MCI from normal cognition (NC), but not so good for differentiating MCI with dementia (Shi et al., 2014). In addition to memory impairment, recent studies confirmed instrumental activities of daily living (IADL) were also affected in patients with MCI. The aim of this study was to investigate the diagnostic validity of combining DSR and IADL for detecting MCI.

Diagnostic Accuracy of the Chinese Version of the Trail-Making Test for Screening Cognitive Impairment

The Trail‐Making Test (TMT), which is commonly used to measure executive function, consists of two components (TMT‐A and TMTB). There is a lack of normative TMT data for Chinese elderly adults. This study aimed to evaluate the validity of the TMT in screening for cognitive impairment.

Efficacy and safety of SQJZ herbal mixtures on nonmotor symptoms in Parkinson disease patients: Protocol for a randomized, double-blind, placebo-controlled trial

Background: As a multisystemic neurodegenerative disorder, Parkinson disease (PD) has a broad spectrum of symptoms including motor and nonmotor symptoms (NMS). As shown in studies, NMS can also impact patients quality of life, and many of them often go untreated. Chinese herbal medicines with multiconstituent may alleviate NMS in PD patients. This research is carried out to assess the efficacy and safety of a Chinese herbal formula for NMS, with its Chinese name acronym of SQJZ. Methods/design: It will be a multicenter, randomized, double-blind, placebo-controlled trial. Idiopathic PD with a Hoehn and Yahr scale score ⩽4, aged 18 to 80 years, will be involved. About 240 patients will be randomly assigned to either SQJZ or placebo in a 2:1 ratio. There is a 2-week run-in period before the randomization, and the follow-up will be 24 weeks, including 12-week treatment period, with visit once every 4 weeks and 12-week washout follow-up. All participants are asked to maintain the regular medication schedule. SQJZ formula will consist of Chinese herbs with effects for insomnia, constipation, anxiety, and so on. The primary outcome will be measured using NMS scale, and secondary outcomes will include unified PD rating scale, PD sleep scale, the Parkinson fatigue scale, the constipation severity instrument, and PD Questionnaire-39. The primary efficacy analysis will be based on the intention-to-treat method, and mixed-model repeated-measures analyses will be used. Discussion: The findings from this research might provide evidence of the efficacy and safety of SQJZ Chinese herbal formula for treating NMS in PD patients. The results will sustain the broader use of SQJZ formula in PD.

Effect of GAPT extract on expression of tau protein and its phosphorylation related enzymes in hippocampal neurons of APPV717I transgenic mice

ObjectiveTo investigate the effect of GAPT, an extract mixture from Radix Ginseng, Rhizoma Acor tatarinowii, Radix Polygalae and Radix Curcuma (containing ingredient of turmeric), etc. on expression of tau protein and its phosphorylation related enzyme in hippocampal neurons of APPV717I transgenic mice.MethodsSixty three-month-old APPV717I transgenic mice were randomly divided into model group, donepezil group [0.92 mg/(kg•d)], the low, medium and high dosage of GAPT groups [0.075, 0.15, 0.30 g/(kg•d), 12 in each group], and 12 three-month-old C57BL/6J mice were set as a normal control group, treatments were administered orally once a day respectively, and both the normal group and model group were given 0.5% sodium carboxymethyl cellulose solution. Immunohistochemistry (IHC) and Western blot analysis were used to detect the expression of total tau protein (Tau-5), cyclin-dependent kinase 5 (CDK5) and protein phosphatase 2A (PP2A) in hippocampal neurons of experimental mice after 8-month drug administration (11 months old).ResultsIn the model group, the expression of Tau-5 and CDK5 were increased, whereas the expression of PP2A was decreased in hippocampal neurons, which were signifificantly different compared with that in the normal group (all P<0.01). IHC test indicated the number and area of either Tau-5 or CDK5 positive cells were decreased with a dose-depended way in GAPT groups, and an increase of PP2A. Compared with the model group, the changes were signifificant in GAPT groups (P<0.05 or P<0.01). Similar results were shown by Western blot.ConclusionGAPT could attenuate abnormal hyperphosphorylation of tau protein in hippocampal neurons of APPV717I transgenic mice via inhibiting the expression of CDK5 and activating the expression of PP2A.

A NEW AGE-BASED CUTOFF OF VISUAL RATING SCALES IN MRI: IMPROVING THE DIAGNOSTIC ACCURACY OF AD IN A CHINESE POPULATION

Background: We investigated the diagnostic accuracy of various white matter hyperintensities(WMH) indexes and DTI measures for diagnosing Alzheimer’s dementia(AD) and compared their impacts on global cognition according to the diagnosis of cognitive status. Methods:Sociodemographic data, neuropsychological tests, 3 Tesla brain MRIs including DTI of 388 subjects(149 cognitive normal(CN), 106 mild cognitive impairment(MCI), 133 AD) were used. The WMHs were segmented automatically using automated monospectral segmentation method forWMHs using FLAIR MRIs. The WMH indexes using Fazekas classification, modified Fazekas classification, 3-dimensional smoothness index, texture index, and combined WMH indexed were examined. Fractional anisotropy, mean diffusivity, axial diffusivity, radial diffusivity of each white matter tract based on JHU ICBM-DTI-81 White-Matter Labels atlas were calculated as DTI measures. Discriminant analysis for classifying CN, MCI, and AD and Receiver Operating Characteristic(ROC) Curve analysis for diagnosing AD were performed. Stepwise linear regression analysis was performed to examine the impacts of WMH indexes and DTI measures on Mini-Mental State Examination(MMSE) score according to the diagnosis. Results: 50.4% for Fazekas classification, 54.0% for modified Fazekas, 60.3% for smoothness index, 59.2% for texture index, 63.5% for combined WMH index, 96.1% for DTI measures, and 96.6% for DTI+WMH index were correctly classified by discriminant analysis. AUCs for diagnosing Alzheimer’s dementia were 0.740 for combinedWMH index, and 1.000 for DTImeasures. Texture indexes based on T1(CN), texture indexes based on FLAIR(MCI) and only DTI measures(AD) were included for stepwise linear regression model with highest R squared value for MMSE score. Conclusions: DTI measures showed superiority for classifying CN/MCI/AD and diagnosing AD than any WMH indexes. However, in CN and MCI groups, the texture index better explained the global cognitive function than the DTI measures. A replication of the results is needed through an independent sample, and the relationship between WHMs, DTI measures, and cognitive function needs to be clarified through longitudinal studies. Funding: This research was supported by Basic Science Research Program through the National Research Foundation of Korea(NRF) funded by the Ministry of Education(2015R1D1A1A01059251) and grant from the Korean Health Technology R&D Project, Ministry of Health and Welfare, Republic of Korea (grant no. HI09C1379).

EFFICACY AND SAFETY OF TIANZHI GRANULE IN MILD TO MODERATE VASCULAR DEMENTIA: A MULTICENTRE, RANDOMIZED, DOUBLE-BLIND, THREE-ARMS TRIAL

Background: Data quality programs that reduce rater error are considered an important component of clinical trials, especially those in Alzheimer’s disease (AD) due to the continued high failure rate in AD drug development (1,2). Data quality programs have historically utilized a standard visit-based schedule of review in conjunction with targeted reviews based on rater performance (3). The addition of a statistically driven approach that targets longitudinal, statistically aberrant variability in the scores of key outcome measures as compared to study means has the potential to identify further data issues that may not have been previously detected using traditional approaches. In this analysis, we evaluated the frequency of scoring and/or administrative errors detected during review of the ADAS-Cog and ADCS-ADL, which had statistically aberrant longitudinal change. Methods: Data was obtained during a multi-national AD clinical trial. For key outcome measures, a data quality program was utilized that included: confirmation that standard administration procedures were followed, scores were transcribed accurately, and standard scoring practices were followed (4). All post-randomization visits with an ADAS-Cog and ADCS-ADL were evaluated for statically abnormal patterns of change. Any scores meeting the a priori criteria as being statistically aberrant were evaluated for adherence to standard administration practices and accurate scoring by an independent expert reviewer. Results were analyzed for frequency and type of error. Results: In total, 6251 post-randomization visits were completed. Based on statistical modeling, 12.00% (n 1⁄4 750) of these visits were considered outliers. When these visits were reviewed, 20% (n 1⁄4 152), had at least one scoring or administrative error on the ADAS-Cog or ADCS-ADL. More specifically, as each visit could contain multiple errors, 175 scoring and administrative errors were identified. A majority of these represented ADAS-Cog scoring errors (n1⁄4 102), whereas less than 8% (n1⁄4 13) represented ADCS-ADL scoring errors. See Table 1 for additional administration and scoring error frequencies for ADAS-Cog and ADCS-ADL. Conclusions: The use of statistical modeling to assist in the identification of assessments that have potentially problematic ratings due to aberrant data patterns is a complementary methodology to traditional means of ensuring data quality.

ADDING CHINESE HERBAL MEDICINE TO CONVENTIONAL THERAPY BRINGS COGNITIVE BENEFITS TO PATIENTS WITH ALZHEIMER’S DISEASE: A TWO-YEAR STUDY

or 10 mg/kg or a titration regimen up to 10 mg/kg [average expected dose, 5.3 mg/kg at 52 weeks]) or placebo once every 4 weeks for 52 weeks in a staggered, ascending-dose design. Randomization in fixed-dose arms was stratified by ApoE4 status (carrier/noncarrier). Baseline to week 54 change in CDR-sum of boxes (CDR-SB) score was an exploratory endpoint. This post hoc analysis assessed cognitive and functional domains of the CDR at the week 54 visit in the overall study population and a subpopulation of patients with early AD defined by CDR global score, 0.5; CDR memory domain score, 0.5; and MMSE score, 24. Results:A total of 196 patients were randomized and dosed in PRIME. In the overall study population, the baseline means for CDR-SB, cognitive domain scores, and functional domain scores were 3.17, 2.00, and 1.17, respectively. At week 54, the adjusted mean changes for the cognitive domain scores were 0.93 (placebo), 0.94 (1 mg/kg), 0.72 (3 mg/kg), 0.49 (6 mg/kg), 0.30 (10 mg/kg), and 0.64 (titration regimen). For functional domain scores, the corresponding adjusted mean changes were 0.91, 0.81, 0.67, 0.62, 0.32, and 0.10. A subanalysis of patients with early AD was consistent with findings from the overall study population. Conclusions: This interim post hoc analysis suggests an effect of aducanumab on both cognitive and functional CDR domain scores at week 54 in the overall study population and in a subset with early AD.

Early detection of amnestic mild cognitive impairment from normal cognition or dementia by neurometabolites of the brain with magnetic resonance spectroscopy in a chinese population

large group of cognitively normal (CN), individuals with mild cognitive impairment (MCI) and Alzheimer’s disease (AD). Methods: 324 CN, 502 individuals with MCI, and 182 with AD were selected from the Alzheimer’s Disease Neuroimaging Initiative database. We included participants only if [18F] florbetapir positron emission tomography (PET), conducted within 3 month of a clinical and cognitive assessment visits, and APOE genotype information is available. To determine main effects and interactions of APOE ε4 and Ab burden on the scores, a series of 2 X 2 analysis of covariance, with age, gender, and education as covariates, was performed. Results: The influence of APOE ε4 status and Ab positivity on cognitive function, clinical severity, and functional status were minimal in CN and AD. In MCI, main effect of APOE ε4 was dominantly observed in executive function, with ε4 carriers exhibiting poorer performances. Ab positivity had no influence over this association. Main effect of Ab positivity was significant in global cognition, memory, and visuospatial ability, with MCI individuals of high Ab burden exhibiting poorer performances. However no single measure of the executive function domain was influenced by Ab positivity (Figure). Interactive effects of Ab positivity and APOE ε4 status were found in the measures of global cognition, verbal recognition memory, and clinical severity. Conclusions:We provided further evidence that APOE ε4 and Ab plays independent and interactive roles in cognitive functions from the large sample of CN, MCI, and AD. In MCI, the influences of APOE ε4and Ab burden status on executive and non-executive functions were found in a manner of dissociable pattern.

The differential diagnosis of amnestic mild cognitive impairment and Alzheimer's disease dementia by hippocampal volume measurement with MR in a chinese population

Figure 2. The correlation between bilateral hippocampal volume and MMSE scores of all subjects. Yeo Jin Kim, Hee Jin Kim, Jae-Hyun Park, Sung Tae Kim, Kyung Han Lee, Jong Min Lee, Jin San Lee, Duk L. Na, Sang Won Seo, Samsung Medical Center, Seoul, South Korea; Hanyang University, Seoul, South Korea; Neuroscience Center, Samsung Medical Center, Seoul, South Korea. Contact e-mail: sangwonseo@empal.com

THE PROTECTIVE EFFECTS OF GEPT ON HIPPOCAMPAL NEURONS AND SYNAPSES OF APP/PS1 TRANSGENIC MICE

Background:Mid-life obesity can increase the risk for developing dementia later in life, particularly Alzheimer’s disease (AD), and experimental diet-induced obesity increases AD-like pathology and/or behavioural deficits in transgenic mouse models of AD. However, most of these experimental studies assess the effect of high fat diet (HFD) in male mice only, and effects in female mice are less clear. Moreover, our previous work has shown that HFD also affects memory in healthy controls and that this effect is gender dependent.Resveratrol (RSV) has recently showed to improve health and life span of mice on a HFD and to improve learning and memory in both aged and AD mice, effects that are thought to be due to its anti-oxidant and/or anti-inflammatory properties. However until now no studies have been done taking into account both AD and co-morbidities (obesity). Therefore, the aim of this study was to test the effect of RSV in female 3xTgADmice fed with a HFD.Methods:Groups of female 3xTgAD and control (Non-Tg) mice w ere maintained on a control (12% fat) or a HFD (60% fat) for 12 months with or without RSV supplementation in the drinking water (5 mg/Kg/day). Body weight (BW) was monitored weekly. Behaviour was assessed at 12 months of treatment using the open-field and Y-maze spontaneous alternation tests. Epididymal fat, brown adipose tissue (BAT) and liver weight were measured after culling.Results: RSV did not affect BW in female 3xTgADmice fed a HFD but a decrease in weight gain was observed in Non-Tg HFD animals. HFD increased epididymal fat and BAT weight in both Non-Tg and 3xTgAD mice, and RSV reversed this effect only in Non-Tg mice. HFD also elevated liver weight in Non-Tg mice, which was reversed by RSV. RSV had no effect on behaviour or memory in both groups. Conclusions: These results suggest that RSV is able to reverse metabolic changes induced by the HFD in female Non-Tg mice but not in 3xTgAD animals, with no effect on behaviour in either. In conclusion, the effect of a HFD on memory is not affected by RSV and therefore is unlikely to be due to changes in oxidative stress and/or inflammation.